The present invention relates to the use of gingival fibroblasts in vascular cell therapy, in particular for the treatment of arterial pathologies.
The arterial wall consists of three superimposed layers called tunicae. The inner tunica (intimae) consists of a layer of endothelial cells. The intermediate tunica (media) consists mainly of smooth muscle fibers and connective tissue rich in elastic fibers. The outer tunica (adventica) is a connective envelope that surrounds the whole assembly.
Arteries are subjected to numerous attacks of various origin (hypoxia, lipid overload, hemodynamic forces, atheroma, hypertension, etc.) that can induce arterial wall lesions. During the repair of these lesions, an abnormal healing reaction can occur, resulting from an imbalance between degradation and synthesis of the extracellular matrix, and inducing pathological arterial remodeling, which can be reflected by a vascular enlargement (aneurism) or, on the other hand, by a constriction (stenosis, occurring secondarily during atherogenesis, or restenosis, subsequent in particular to an angioplasty, evolving in the course of cicatricial remodeling toward the reappearance of a stenosis).
For example, in aneurismal lesions, enzymatic degradation of the extracellular matrix components, in particular of the elastic fibers, and a decrease in the number of smooth muscle cells (SMCs) are observed in the media; a fibrosis accompanied by considerable inflammatory infiltration is observed in the adventica.
The degradation of the extracellular matrix components involves various matrix proteases. Among these, mention may in particular be made of an elastase, matrix metalloproteinase-9 (MMP9) synthesized by the infiltrated leukocytes and the physiological host cells (endothelial cells, smooth muscle cells and adventitial fibroblasts), and which is in large part responsible for the elastic fiber fragmentation (THOMPSON, J. Clin. Invest. 96: 318-326, 1995). In parallel, the increased sparcity of the SMCs in the media leads to a decrease in the synthesis of the extracellular matrix components, and in that of matrix protease inhibitors, which are mainly synthesized by these SMCs (LOPEZ-CANDALES et al., Am. J. Pathol. 150: 993-1007, 1997).
In the case of stenosis and of restenosis a retractile fibrous remodeling occurs, which can also be considered to be an abnormal wound healing process. This remodeling is characterized by intimal fibrous hyperplasia (LAFONT et al., Circ. Res. 76(6): 996-1002, 1995), and appears to be related to an increase in collagen in the neointima, in the media and in the adventica (LAFONT et al., Circulation 100(10): 1109-1115, 1999; DURAND et al., Arch. Mal. Coeur Vaiss. 94(6): 605-611, 2001).
At the current time, the treatment of arterial pathologies is mainly based on surgery and cardiology procedures (vascular surgery, aortocoronary and peripheral bypasses, aortic dacron prostheses, coronary and peripheral artery angioplasty, aortic endoprostheses, etc.). However, these invasive techniques do not treat the cause, but the consequences of the pathology. They make it possible to improve the patient's situation without being able to curb the development of the disease.
It therefore appears to be necessary to have new means of treatment that are less invasive and that make it possible to effectively treat the pathological arterial remodeling.
ALLAIRE et al. (J. Clin. Invest. 102(7): 1413-1420, 1998) have observed, in an experimental aneurism model in rats, that local implantation of SMCs in the arterial wall induces an inhibition of elastic fiber degradation and of the formation of an aneurism. It has also been shown, in rats, that already formed experimental aneurisms can be stabilized by the local injection of SMCs. This stabilization is associated with secretion of TGFβ of paracrine origin at the level of the cell transplant (LOSY et al., J. Vasc. Surg. 37(6): 1301-1309, 2003).
However, a major obstacle to the use of SMCs for the treatment of aneurisms by cell therapy comes from the need to obtain these SMCs from stem cells. The stem cells used come from the marrow or the blood and are very difficult to obtain.